Controlled release metformin formulations

ABSTRACT

Sustained release pharmaceutical formulations comprising an antihyperglycemic drug or a pharmaceutically acceptable salt thereof are disclosed. The formulations provide therapeutic plasma levels of the antihyperglycemic drug to a human patient over a 24 hour period after administration.

The present application is a continuation of U.S. Ser. No. 09/726,193,filed Nov. 29, 2000 now abandoned, which is a continuation of U.S. Ser.No. 09/594,637 filed Jun. 15, 2000 now abandoned, which is acontinuation of U.S. Ser. No. 09/045,330 filed Mar. 20, 1998, now issuedas U.S. Pat. No. 6,099,859, the disclosures of which are herebyincorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to controlled release unit doseformulations containing an antihyperglycemic drug. More specifically,the present invention relates to an oral dosage form comprising abiguanide such as metformin or buformin or a pharmaceutically acceptablesalt thereof such as metformin hydrochloride or the metformin saltsdescribed in U.S. Pat. Nos. 3,957,853 and 4,080,472 which areincorporated herein by reference.

In the prior art, many techniques have been used to provide controlledand extended-release pharmaceutical dosage forms in order to maintaintherapeutic serum levels of medicaments and to minimize the effects ofmissed doses of drugs caused by a lack of patient-compliance.

In the prior art are extended release tablets which have an osmoticallyactive drug core surrounded by a semipermeable membrane. These tabletsfunction by allowing a fluid such as gastric or intestinal fluid topermeate the coating membrane and dissolve the active ingredient so itcan be released through a passageway in the coating membrane or if theactive ingredient is insoluble in the permeating fluid, pushed throughthe passageway by an expanding agent such as a hydrogel. Somerepresentative examples of these osmotic tablet systems can be found inU.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and 4,783,337.U.S. Pat. No. 3,952,741 teaches an osmotic device wherein the activeagent is released from a core surrounded by a semipermeable membraneonly after sufficient pressure has developed within the membrane toburst or rupture the membrane at a weak portion of the membrane.

The basic osmotic device described in the above cited patents have beenrefined over time in an effort to provide greater control of the releaseof the active ingredient. For example U.S. Pat. Nos. 4,777,049 and4,851,229, describe an osmotic dosage form comprising a semipermeablewall surrounding a core. The core contains an active ingredient and amodulating agent wherein the modulating agent causes the activeingredient to be released through a passageway in the semipermeablemembrane in a pulsed manner. Further refinements have includedmodifications to the semipermeable membrane surrounding the active coresuch as varying the proportions of the components that form themembrane, i.e U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625 orincreasing the number of coatings surrounding the active core, i.e5,650,170 and 4,892,739.

Although vast amounts of research has been performed on controlled orsustained release compositions and in particular on osmotic dosageforms, very little research has been performed in the area of controlledor sustained release compositions that employ antihyperglycemic drugs.

The limited work on controlled or sustained release formulations thatemploy antihyperglycemic drugs such as metformin hydrochloride has beenlimited to the combination of the antihyperglycemic drug and anexpanding or gelling agent to control the release of the drug from thedosage form. This limited research is exemplified by the teachings of WO96/08243 and by the GLUCOPHAGE® product which is a commerciallyavailable product from Bristol-Myers Squibb Co. containing metforminHCl.

It is reported in the 50th Edition of the Physicians' Desk Reference,copyright 1996, p. 753, that food decreases the extent and slightlydelays the absorption of metformin delivered by the GLUCOPHAGE® dosageform. This decrease is shown by approximately a 40% lower peakconcentration and a 25% lower AUC in plasma and a 35 minute prolongationof time to peak plasma concentration following administration of asingle GLUCOPHAGE® tablet containing 850 mg of metformin HCl with foodcompared to the similar tablet administered under fasting conditions.

It is an object of the present invention to provide a controlled orsustained release formulation for an antihyperglycemic drug wherein thebioavailability of the drug is not decreased by the presence of food.

It is a further object of the present invention to provide a controlledor sustained release formulation for an antihyperglycemic drug that doesnot employ an expanding polymer.

It is also a further object of the present invention to provide acontrolled or sustained release formulation for an antihyperglycemicdrug that can provide continuous and non-pulsating therapeutic levels ofan antihyperglycemic drug to an animal or human in need of suchtreatment over a twelve hour to twenty-four hour period.

It is an additional object of the present invention to provide acontrolled or sustained release formulation for an antihyperglycemicdrug that obtains peak plasma levels approximately 8-12 hours afteradministration.

It is also an object of this invention to provide a controlled orsustained release pharmaceutical tablet having only a homogeneousosmotic core wherein the osmotic core component may be made usingordinary tablet compression techniques.

SUMMARY OF THE INVENTION

The foregoing objectives are met by a controlled release dosage formcomprising:

-   -   (a) a core comprising:        -   (i) an antihyperglycemic drug;        -   (ii) optionally a binding agent; and        -   (iii) optionally an absorption enhancer;    -   (b) a semipermeable membrane coating surrounding the core; and    -   (c) at least one passageway in the semipermeable membrane.

The dosage form of the present invention can provide therapeutic levelsof the antihyperglycemic drug for twelve to twenty-four hour periods anddoes not exhibit a decrease in bioavailability if taken with food. Infact, a slight increase in the bioavailability of the antihypoglycemicdrug is observed when the controlled release dosage form of the presentinvention is administered with food. In a preferred embodiment, thedosage form will be administered once a day, ideally with or after ameal and most preferably with or after the evening meal, and providetherapeutic levels of the drug throughout the day with peak plasmaslevels being obtained between 8-12 hours after administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph which depicts the dissolution profile in simulatedintestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid(SGF) of the formulation described in Example 1 as tested according tothe procedure described in United States Pharmacopeia XXIII, Apparatus 2@ 75 rpm.

FIG. 2 is a graph which depicts the dissolution profile in simulatedintestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid(SGF) of the formulation described in Example 2 as tested according tothe procedure described in United States Pharmacopeia XXIII, Apparatus 2@ 75 rpm.

FIG. 3 is a graph which depicts the dissolution profile in simulatedintestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid(SGF) of the formulation described in Example 3 as tested according tothe procedure described in United States Pharmacopeia XXIII, Apparatus 2@ 75 rpm.

FIG. 4 is a graph depicting the in vivo metformin plasma profile of theformulation described in Example 1 and the in vivo metformin plasmaprofile of the commercially available metformin HCl product GLUCOPHAGE®under fasting conditions.

FIG. 5 is a graph depicting the in vivo metformin plasma profile of theformulation described in Example 2 and the in vivo metformin plasmaprofile of the commercially available metformin HCl product GLUCOPHAGE®under fasting conditions.

FIG. 6 is a graph depicting the in vivo metformin plasma profile of theformulation described in Example 2 and the in vivo metformin plasmaprofile of the commercially available metformin HCl product GLUCOPHAGE®under fed conditions.

FIG. 7 is a graph depicting the in vivo metformin plasma profile of theformulation described in Example 3 and the in vivo metformin plasmaprofile of the commercially available metformin HCl product GLUCOPHAGE®under fed conditions (after breakfast).

FIG. 8 is a graph depicting the in vivo metformin plasma profile of theformulation described in Example 3 and the in vivo metformin plasmaprofile of the commercially available metformin HCl product GLUCOPHAGE®under fed conditions (after dinner).

DETAILED DESCRIPTION OF THE INVENTION

The term antihyperglycemic drugs as used in this specification refers todrugs that are useful in controlling or managing noninsulin-dependentdiabetes mellitus (NIDDM). Preferably, the antihyperglycemic drug is abiguanide such as metformin or buformin or a pharmaceutically acceptablesalt thereof such as metformin hydrochloride.

The binding agent may be any conventionally known pharmaceuticallyacceptable binder such as polyvinyl pyrrolidone, hydroxypropylcellulose, hydroxyethyl cellulose, ethylcellulose, polymethacrylate,waxes and the like. Mixtures of the aforementioned binding agents mayalso be used. The preferred binding agents are water soluble such aspolyvinyl pyrrolidone having a weight average molecular weight of 25,000to 3,000,000. The binding agent comprises approximately about 0 to about40% of the total weight of the core and preferably about 3% to about 15%of the total weight of the core.

The core may optionally comprise an absorption enhancer. The absorptionenhancer can be any type of absorption enhancer commonly known in theart such as a fatty acid, a surfactant, a chelating agent, a bile saltor mixtures thereof. Examples of some preferred absorption enhancers arefatty acids such as capric acid, oleic acid and their monoglycerides,surfactants such as sodium lauryl sulfate, sodium taurocholate andpolysorbate 80, chelating agents such as citric acid, phytic acid,ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis(β-aminoethyl ether)-N,N,N,N-tetraacetic acid (EGTA). The core comprisesapproximately 0 to about 20% of the absorption enhancer based on thetotal weight of the core and most preferably about 2% to about 10% ofthe total weight of the core.

The core of the present invention which comprises the antihyperglycemicdrug, the binder which preferably is a pharmaceutically acceptable watersoluble polymer and the absorption enhancer is preferably formed by wetgranulating the core ingredients and compressing the granules with theaddition of a lubricant into a tablet on a rotary press. The core mayalso be formed by dry granulating the core ingredients and compressingthe granules with the addition of a lubricant into tablets or by directcompression.

Other commonly known excipients may also be included into the core suchas lubricants, pigments or dyes.

The homogeneous core is coated with a semipermeable membrane; preferablya modified polymeric membrane to form the controlled release tablet ofthe invention. The semipermeable membrane is permeable to the passage ofan external fluid such as water and biological fluids and is impermeableto the passage of the antihyperglycemic drug in the core. Materials thatare useful in forming the semipermeable membrane are cellulose esters,cellulose diesters, cellulose triesters, cellulose ethers, celluloseester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate, and cellulose acetatebutyrate. Other suitable polymers are described in U.S. Pat. Nos.3,845,770, 3,916,899, 4,008,719, 4,036,228 and 4,11210 which areincorporated herein by reference. The most preferred semipermeablemembrane material is cellulose acetate comprising an acetyl content of39.3 to 40.3%, commercially available from Eastman Fine Chemicals.

In an alternative embodiment, the semipermeable membrane can be formedfrom the above-described polymers and a flux enhancing agent. The fluxenhancing agent increases the volume of fluid imbibed into the core toenable the dosage form to dispense substantially all of theantihyperglycemic drug through the passageway and/or the porousmembrane. The flux enhancing agent can be a water soluble material or anenteric material. Some examples of the preferred materials that areuseful as flux enhancers are sodium chloride, potassium chloride,sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propyleneglycol, hydroxypropyl cellulose, hydroxypropyl methycellulose,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.The preferred flux enhancer is PEG 400.

The flux enhancer may also be a drug that is water soluble such asmetformin or its pharmaceutically acceptable salts or a drug that issoluble under intestinal conditions. If the flux enhancer is a drug, thepresent dosage form has the added advantage of providing an immediaterelease of the drug which is selected as the flux enhancer.

The flux enhancing agent comprises approximately 0 to about 40% of thetotal weight of the coating, most preferably about 2% to about 20% ofthe total weight of the coating. The flux enhancing agent dissolves orleaches from the semipermeable membrane to form paths in thesemipermeable membrane for the fluid to enter the core and dissolve theactive ingredient.

The semipermeable membrane may also be formed with commonly knownexcipients such a plasticizer. Some commonly known plasticizers includeadipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate,triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate,citric acid esters, and those described in the Encyclopedia of PolymerScience and Technology, Vol. 10 (1969), published by John Wiley & Sons.The preferred plasticizers are triacetin, acetylated monoglyceride,grape seed oil, olive oil, sesame oil, acetyltributylcitrate,acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate,diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate,dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate,and the like. Depending on the particular plasticizer, amounts of from 0to about 25%, and preferably about 2% to about 15% of the plasticizercan be used based upon the total weight of the coating.

As used herein the term passageway includes an aperture, orifice, bore,hole, weaken area or an erodible element such as a gelatin plug thaterodes to form an osmotic passageway for the release of theantihyperglycemic drug from the dosage form. A detailed description ofthe passageway can be found in U.S. Pat. Nos. 3,845,770, 3,916,899,4,034,758, 4,077,407, 4,783,337 and 5,071,607.

Generally, the membrane coating around the core will comprise from about1% to about 5% and preferably about 2% to about 3% based on the totalweight of the core and coating.

In an alternative embodiment, the dosage form of the present inventionmay also comprise an effective amount of the antihyperglycemic drug thatis available for immediate release. The effective amount ofantihyperglycemic drug for immediate release may be coated onto thesemipermeable membrane of the dosage form or it may be incorporated intothe semipermeable membrane.

In a preferred embodiment the dosage form will have the followingcomposition:

Preferred Most Preferred CORE: drug 50-98%  75-95%  binder 0-40% 3-15%absorption enhancer 0-20% 2-10% COATING: semipermeable polymer 50-99% 75-95%  flux enhancer 0-40% 2-20% plasticizer 0-25% 2-15%

The dosage forms prepared according to the present invention shouldexhibit the following dissolution profile when tested in a USP type 2apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5phosphate buffer) and at 37° C.:

Time (hours) Preferred Most Preferred 2   0-25% 0-15% 4  10-45% 20-40% 8 30-90% 45-90% 12 NTL 50% NTL 60% 16 NTL 60% NTL 70% 20 NTL 70% NTL 80%NTL = NOT LESS THAN

In the preparation of the tablets of the invention, various conventionalwell known solvents may be used to prepare the granules and apply theexternal coating to the tablets of the invention. In addition, variousdiluents, excipients, lubricants, dyes, pigments, dispersants etc. whichare disclosed in Remington's Pharmaceutical Sciences, 1995 Edition maybe used to optimize the formulations of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Example 1

A controlled release tablet containing 850 mg of metformin HCl andhaving the following formula is prepared as follows:

I Core metformin HCl 90.54% povidone¹, USP 4.38% sodium tribasicphosphate 4.58% magnesium stearate 0.5% ¹approximate molecular weight =50,000; dynamic viscosity (10% w/v solution at 20° C.) = 5.5-8.5 m Pa s.

(a) Granulation

The metformin HCl is delumped by passing it through a 40 mesh screen andcollecting it in a clean, polyethylene-lined container. The povidone,K-30, and sodium tribasic phosphate are dissolved in purified water. Thedelumped metformin HCl is then added to a top-spray fluidized bedgranulator and granulated by spraying the binding solution of povidoneand sodium tribasic phosphate under the following conditions: inlet airtemperature of 50-70° C.; atomization air pressure of 1-3 bars; andspray rate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

(c) Seal Coating (optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained.

II Sustained Release Coating cellulose acetate (398-10)² 85% triacetin 5% PEG 400 10% ²acetyl content 39.3-40.3%

(d) Sustained Release Coating

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars; and spray rate of 120-150 ml/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

The resulting tablet is tested in simulated intestinal fluid (pH 7.5)and simulated gastric fluid (SGF) according to the procedure describedin United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm and found tohave the following release profile:

TIME (hours) % Released (SGF) % Released (pH 7.5) 2 9 12 4 27 32 8 62 8212 82 100 16 88 105 20 92 108

The release profile in pH 7.5 and SGF of the sustained release productprepared in this Example is shown in FIG. 1.

FIG. 4 depicts the in vivo metformin plasma profile of the sustainedrelease product prepared in this Example. Also shown in FIG. 4 is the invivo metformin plasma profile of GLUCOPHAGE®, a commercially availablepharmaceutical product containing the drug metformin HCl.

Example 2

A controlled release tablet containing 850 mg of metformin HCl andhaving the following formula is prepared as follows:

I Core metformin HCl 88.555% povidone³, USP 6.368% sodium lauryl sulfate4.577% magnesium stearate 0.5% ³approximate molecular weight =1,000,000, dynamic viscosity (10% w/v solution at 20° C.) = 300-700 m Pas.

(a) Granulation.

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone, K-90F, is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C.; atomization air pressureof 1-3 bars; and spray rate of 10-100 ml/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the coated granules are compressed ona rotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

(c) Seal Coating (optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained.

II Sustained Release Coating cellulose acetate (398-10)⁴ 85% triacetin 5% PEG 400 10% ⁴acetyl content 39.3-40.3%

(d) Sustained Release Coating

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars; and spray rate of 120-150 ml/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

The resulting tablet is tested in simulated intestinal fluid (pH 7.5)and simulated gastric fluid (SGF) according to the procedure describedin United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm and found tohave the following release profile:

TIME (hours) % Released (SGF) % Released (pH 7.5) 2 13 12 4 29 27 8 5552 12 72 71 16 81 83 20 87 91

The release profile in pH 7.5 and SGF of the sustained release productprepared in this Example is shown in FIG. 2.

FIG. 5 depicts the in vivo metformin plasma profile of the sustainedrelease product prepared in this Example under fasting conditions. FIG.5 also shows the in vivo metformin plasma profile of the GLUCOPHAGE®product under fasting conditions.

FIG. 6 depicts the in vivo metformin plasma profile of the sustainedrelease product prepared in this Example under fed conditions. FIG. 6also shows the in vivo metformin plasma profile of the GLUCOPHAGE®product under fed conditions.

FIGS. 5 and 6 clearly show that the dosage forms prepared in accordancewith the present invention exhibit consistent bioavailability under bothfed and fasting conditions while the GLUCOPHAGE® product'sbioavailability decreases in the presence of food.

Example 3

A controlled release tablet containing 850 mg of metformin HCl andhaving the same formula as in Example 2 is prepared as described inExample 2 except that an additional hole was drilled on the plain sideof the coated tablet. The additional hole had a diameter ofapproximately 1 mm.

The resulting tablet is tested in simulated intestinal fluid (pH 7.5)and simulated gastric fluid (SGF) according to the procedure describedin United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm and found tohave the following release profile:

TIME (hours) % Released (SGF) % Released (pH 7.5) 2 13 14 4 27 28 8 5063 12 67 84 16 84 95 20 97 102

The release profile in pH 7.5 and SGF of the sustained release productprepared in this Example is shown in FIG. 3.

FIG. 7 depicts the in vivo metformin plasma profile of the sustainedrelease product prepared in this Example when administered shortly afterbreakfast. FIG. 7 also shows the in vivo metformin plasma profile of theGLUCOPHAGE® product administered shortly after breakfast.

FIG. 8 depicts the in vivo metformin plasma profile of the sustainedrelease product prepared in this Example when administered shortly afterdinner. FIG. 8 also shows the in vivo metformin plasma profile of theGLUCOPHAGE® product administered shortly after dinner.

Table 1 is a summary of the bioavailability comparision data,test/reference ratio, shown in FIGS. 4-8 wherein the GLUCOPHAGE® productis the reference product in a two way crossover biostudy with n=6.

TABLE 1 Formula Figure Study AUC Cmax Tmax Ex. 1 4 Fasting 0.202 0.122.15 Ex. 2 5 Fasting 0.369 0.214 1.73 Ex. 2 6 Fed (bkft) 0.628 0.3051.94 Ex. 3 7 Fed (bkft) 0.797 0.528 1.82 Ex. 3 8 Fed (dinner) 0.8500.751 2.00 bkft = breakfast

The results reported in Table 1 and FIGS. 4-8 show that dosage formsprepared in accordance with the present invention exhibit an increase inthe bioavailability of the antihyperglycemic drug in the presence offood, especially when taken with or shortly after the evening meal.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1. A method of treating a human diabetic patient with an oral solidsustained release tablet of metformin hydrochloride, comprising:administering the sustained release tablet to the human diabetic patientonce a day under fed conditions, wherein the sustained release tabletcomprises (i) metformin hydrochloride and (ii) a sustained releasematerial, wherein the tablet does not employ an expanding polymer, thesustained release tablet provides therapeutic plasma levels of saidmetformin to the human patient over a 12 to 24 hour period afteradministration; and the sustained release tablet exhibits the followingin vitro dissolution profile when tested in a USP Type 2 apparatus at 75rpms in 900 ml of a pH 7.5 phosphate buffer and 37° C.: 0-25% of themetformin is released after 2 hours; 10-45% of the metformin is releasedafter 4 hours; 30-90% of the metformin is released after 8 hours; notless than 50% of the metformin is released after 12 hours; not less than60% of the metformin is released after 16 hours and not less than 70% ofthe metformin is released after 20 hours.
 2. The method as defined inclaim 1 wherein the tablet exhibits the following in vitro dissolutionprofile when tested in a USP Type 2 apparatus at 75 rpms in 900 ml of apH 7.5 phosphate buffer and 37° C.: 0-15% of the metformin is releasedafter 2 hours; 20-40% of the metformin is released after 4 hours; 45-90%of the metformin is released after 8 hours; not less than 60% of themetformin is released after 12 hours; not less than 70% of the metforminis released after 16 hours and not less than 80% of the metformin isreleased after 20 hours.
 3. The method of claim 1 wherein the tablet isadministered with or after a meal.
 4. The method of claim 1 wherein thetablet is administered with or after evening meal.
 5. The method ofclaim 1 wherein the tablet is an osmotic tablet with a homogeneousosmotic core.